The present invention relates to a nasal preparation which contains a novel aminoguanidine hydrazone derivative and the like. A nasal preparation according to the present invention has a prophylactic and therapeutic effect on myocardial infarction and accompanying dysfunctions, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA (percutaneous transluminal coronary angioplasty), hypertension and accompanying tissue failures and the like, since its active ingredient, i.e., amino guanidine hydrazone derivative, has a sodium-proton (Naxe2x80x94H) exchange inhibiting activity.
While various pharmaceuticals were developed and employed in clinical practice widely, most of them are employed as oral or injectable preparations. An injectable preparation is employed instead of an oral preparation, when an active ingredient is poorly absorbed orally due to an instability in a digestive tract, a poor migration through the wall of a digestive tract and a disadvantageous first pass effect, or when an active ingredient has a digestive tract tissue damaging effect, or when a pharmacological effect should be exerted instantaneously. However, administration via an injection poses a substantial pain to a patient and a substantial inconvenience due to the impossibility of being performed by a patient himself, and becomes problematic especially when the treatment is prolonged.
A nasal administration is an attractive non-injection method for administering an agent conveniently. A nasal administration is advantageous because it can be performed by a patient himself and also because it is scarcely subjected to a metabolism in a liver (first-pass effect) due to a direct introduction of an agent into a systemic blood circulation, and also advantageous because it may exhibit a rapid pharmacological effect due to a generally rapid absorption of an agent once given nasally.
On the other hand, an Naxe2x80x94H exchange inhibitor which is considered to have an improving effect or a cell protecting effect on a cytopathy under an ischemic condition (especially on a myocardial cell) is an attractive agent in the field of the treatment of ischemic diseases.
Various acylguanidine derivatives are disclosed as Naxe2x80x94H exchange inhibitors in JP-A-6-228082, WO96/04241, EP708091 and EP708088.
JP-A-6-509798 discloses a pyrazine derivative represented by the formula: 
wherein R1 is H or a C1-6 alkyl, R2 is 1-morpholinyl, an optionally substituted C1-6 alkyl and the like, R3, R4, R5 and R4 are same or different and each denotes hydrogen, a C1-6 alkyl or benzyl as an agent which has an Naxe2x80x94H exchange inhibiting effect and which may be administered as a nasal preparation.
JP-A-9-504535 discloses a benzoylguanidine derivative represented by the formula: 
wherein A is xe2x80x94CmH2mxe2x80x94NR4xe2x80x94 and the like, R1 is F, Cl, CF3, R1xe2x80x94SO2xe2x80x94 or R1xe2x80x94NHxe2x80x94SO2xe2x80x94 (in which R1 is a C1-5 alkyl, halogen- or phenyl-substituted C1-5 alkyl and the like), R2 is a group represented by the formula: 
and R3, R4 and R5 are same or different and each denotes hydrogen or a C1-4 alkyl and the like as an agent which has an Naxe2x80x94H exchange inhibiting effect and which may be administered as nose drops if possible.
JP-A-9-505035 discloses a pyrazine carboxyamide derivative represented by the formula: 
wherein A is xe2x80x94CmH2mxe2x80x94NR4xe2x80x94 and the like which is bound via a nitrogen atom to a pyrazine carboxyamide system, R1 is hydrogen, fluorine, chlorine, a C1-4 alkyl and the like, R2 is a group represented by the formula: 
and R3, R4 and R4xe2x80x2 are same or different and each denotes hydrogen or a C1-4 alkyl and the like as an agent which has an Naxe2x80x94H exchange inhibiting effect and which may be administered as nose drops if possible.
WO98/19682 discloses an aminosterol compound represented by the formula: 
as an agent which has an Naxe2x80x94H exchange inhibiting effect and which can be administered to a nasal cavity.
An objective of the present invention is to provide a nasal preparation which exerts an excellent effect as a prophylactic and therapeutic agent for myocardial infarction and accompanying dysfunctions, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA, hypertension and accompanying tissue failures and the like and is a sufficiently satisfactory pharmaceutical composition when compared with an oral preparation or an injectable preparation.
The present inventors have studied nasal preparations intensively for obtaining a prophylactic and therapeutic agent described above. As a result, it has been found that a novel aminoguanidine hydrazone compound represented by the formula (I): 
wherein Ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic ring, Ring B is an optionally substituted 5- or 6-membered aromatic homocyclic or heterocyclic ring, R1 is a hydrogen atom, a hydroxyl group or a lower alkyl group, and n is 0 or 1, or a salt thereof (hereinafter abbreviated as Compound (I)) exhibits an excellent Naxe2x80x94H exchange inhibiting activity (especially NHE-1 selective Naxe2x80x94H exchange inhibiting activity) as well as an excellent in vivo absorption via a nasal mucosa and an excellent migration into a heart, and exerts an unexpectedly excellent pharmacological activity, when used in a nasal preparation, which is comparable with an oral or injectable preparation and is satisfactory characteristically as a medicine, whereby establishing the present invention.
Thus, the present invention relates to:
(1) a nasal preparation comprising a compound represented by the formula (I) or a prodrug thereof;
(2) the nasal preparation as described in the above (1), wherein Ring A is a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring containing 1 or 2 nitrogen atoms optionally substituted by an optionally halogenated C1-6 alkyl or an optionally halogenated C1-6 alkoxy, Ring B is a 5- or 6-membered aromatic homocyclic or heterocyclic ring optionally containing one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen atoms which is optionally substituted by a halogen atom, an optionally halogenated C1-6 alkyl, a hydroxyl group or an optionally halogenated C1-6 alkoxy, R1 is a hydrogen atom or a hydroxyl group, and n is 1;
(3) the nasal preparation as described in the above (1) comprising (xc2x1)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; (xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (xc2x1)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(4) the nasal preparation as described in the above (1) comprising (S)-(xe2x88x92)-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; (S)-(xe2x88x92)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (S)-(xe2x88x92)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(5) the nasal preparation as described in the above (1) which is a prophylactic and therapeutic agent for an ischemic heart disease;
(6) the nasal preparation as described in the above (1), wherein said ischemic heart disease is myocardial infarction, unstable angina or arrhythmia;
(7) the nasal preparation as described in the above (1) which is a prophylactic and therapeutic agent for cardiac insufficiency;
(8) (S)-(xe2x88x92)-7-(5-Fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(9) (S)-(xe2x88x92)-7-(2-Chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(10) a pharmaceutical composition comprising (S)-(xe2x88x92)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (S)-(xe2x88x92)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(11) the composition as described in the above (10) which is an Naxe2x80x94H exchange inhibitor;
(12) the composition as described in the above (10) which is a nasal preparation;
(13) the composition as described in the above (10) which is a prophylactic and therapeutic agent for an ischemic heart disease;
(14) the composition as described in the above (13), wherein said ischemic heart disease is myocardial infarction, unstable angina or arrhythmia;
(15) the composition as described above in the above (10) which is a prophylactic and therapeutic agent for cardiac insufficiency;
(16) use of (S)-(xe2x88x92)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (S)-(xe2x88x92)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof for manufacturing an Naxe2x80x94H exchange inhibitor; and,
(17) a method for inhibiting an Naxe2x80x94H exchange in mammals comprising administering an effective amount of (S)-(xe2x88x92)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (S)-(xe2x88x92)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof to said mammals.